Pioglitazone, a peroxisome proliferator-activated receptor-gamma activator, attenuates atrial fibrosis and atrial fibrillation-promotion

• Project/Area Number: 18590766
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Nagoya University
• Principal Investigator: INDEN Yasuya Nagoya University, Hospital, Associate Professor (10359747)
• Co-Investigator(Kenkyū-buntansha): MUROHARA Toyoaki Nagoya University, Graduate School of Medicine, Professor (90299503) ; TSUJI Yukiomi Nagoya University, Resarch Institute of Enviromental Medicine, Assistant Associate (60432217) ; MAEDA Kengo Nagoya University, University Hospital, Assistant Associate (80456673) ; 近藤 隆久 名古屋大学, 医学部附属病院, 講師 (00303644)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: PPAR γ activator / atrial fibrillation / myocardial fibrosis / heart failure / PARγアゴニスト / 心房筋線維化

Research Abstract

The purpose of this study was to assess the effects of pioglitazone on arrhythmogenic atrial structural remodeling versus the effects of the angiotensin II type 1 receptor blocker candesartan in a rabbit model of congestive heart failure.Rabbits subjected to ventricular tachypacing at 380 to 400 bpm for 4 weeks in the absence and presence of treatment with pioglitazone, candesartan, and combined pioglitazone and candesartan were assessed by electrophysiologic study, atrial fibrosis measurements, and cytokine expression analyses.Atrial fibrillation(AF) lasting longer than 2 seconds was induced in no nonpaced controls but in all ventricular tachypacing-only rabbits(mean duration of AF : 8.0 ± 1.4 seconds). Pioglitazone reduced the duration of AF(33 ± 0.2 seconds, P <.05)and attenuated atrial structural remodeling, with significant reductions in interatrial activation time (50 ± 2 ms vs 41 ± 2 ms, P <.05) and atrial fibrosis(16.8% ± 0.8% vs 10.9% ± 0.7%, P <.05 ; control 1.6% ± 0.2%), effects comparable to those of candesartan(duration of AF : 3.0 ± 0.2 seconds ; activation time 44 ± 2 ms ; fibrosis : 9.4% ± 0.6%). Both pioglitazone and candesartan reduced transforming growth factor-al, tumor necrosis factor-o, and activated extracellular signal-regulated kinase expression similarly, but neither affected p38-kinase or c-Jun N-terminal kinase activation. The effects of combined pioglitazone and candesartan therapy were not significantly different from the effects of pioglitazone or candesartan alone.
Pioglitazone can attenuate congestive heart failure-induced atrial structural remodeling and AF promotion, with effects similar to those of candesartan. PPAR u may be a potential therapeutic target for human AF.

Research Products

• [Journal Article] Pioglitazone, a peroxisome proliferator-activated receptor-gamma activator, attenuates atrial fibrosis and atrial fibrillation promotion in rabbits with congestive heart failure (2008)
  • Author(s): Shimano M
  • Journal Title: Heart Rhythm 5 Pages: 451-459
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Efficacy of pulmonary vein isolation in paroxysmal atrial fibrillation patients with a brugada electrocardiogram. (2008)
  • Author(s): Yamada T
  • Journal Title: Circ J 72 Pages: 281-286
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Pioglitazone, a peroxisome proliferator-activated receptor-gamma activator, attenuates atrial fibrosis and atrial fibrillation promotion in rabbits with congestive heart failure (2008)
  • Author(s): Shimano, M, Tsuji, Y, Inden, Y, Kitamura, K, Uchikawa, T, Harata, S, Nattel, S, Murohara, T
  • Journal Title: Heart Rhythm 5(3) Pages: 451-459
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Efficacy of pulmonary vein isolation in paroxysmal atrial fibrillation patients with a brugada electrocardiogram (2008)
  • Author(s): Yamada, T, Yoshida, Y, Tsuboi, N, Murakami, Y, Okada, T, McElderry, HT, Yoshida, N, Doppalapudi, H, Epstein, AE, Plumb, VJ, Inden, Y, Murohara, T, Kay, GN
  • Journal Title: Circ J 72(2) Pages: 28128-6
  • NAID: 110006571057
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Non-pulmonary vein epicardial foci of atrial fibrillation identified in the left atrium after pulmonary vein isolation (2007)
  • Author(s): Yamada T
  • Journal Title: Pacing Clin Electrophysiol 30 Pages: 1323-1330
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Electrophysiologic and electrocardiographic characteristics and radiofre quency catheter ablation of focal atrial tachycardia originating from the left atrial appendage (2007)
  • Author(s): Yamada T
  • Journal Title: Heart Rhythm. 4 Pages: 1284-1291
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Preferential conduction across the ventricular outflow septum in ventricular arrhythmias originating from the aortic sinus cusp. (2007)
  • Author(s): Yamada T
  • Journal Title: J Am Coll Cardiol 50 Pages: 884-891
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Acute and chronic effects of cardiac resynchronization in patients developing heart failure with long-term pacemaker therapy for acquired complete atrioventricular block. (2007)
  • Author(s): Shimano M
  • Journal Title: Europace 10 Pages: 869-874
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Electrophysiologic characteristics and outcome of segmental ostial superior vena cava isolation in patients with paroxysmal atrial fibrillation initiated by superior vena cava ectopy: comparison with pulmonary vein isolation (2007)
  • Author(s): Muto M
  • Journal Title: J Electrocardiol 40 Pages: 319-325
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Prevalence and severity of left atrial edema detected by electron beam tomography early after pulmonary vein ablation. (2007)
  • Author(s): Okada T
  • Journal Title: J Am Coll Cardiol 49 Pages: 1436-1442
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Non-pulmonary vein epicardial foci of atrial fibrillation identified in the left atrium after pulmonary vein isolation (2007)
  • Author(s): Yamada, T, Murakami, Y, Okada, T, Yoshida, N, Ninomiya, Y, Toyama, J, Yoshida, Y, Tsuboi, N, Inden, Y, Hirai, M, Murohara, T, McElderry, HT, Epstein, AE, Plumb, VJ, Kay, GN
  • Journal Title: Pacing Clin Electrophysiol 30(11) Pages: 1323-1330
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Electrophysiologic and electrocardiographic characteristics and radiofrequency catheter ablation of focal atrial tachycardia originating from the left atrial appendage (2007)
  • Author(s): Yamada, T, Murakami, Y, Yoshida, Y, Okada, T, Yoshida, N, Toyama, J, Tsuboi, N, Inden, Y, Hirai, M, Murohara, T, McElderry, HT, Epstein, AE, Plumb, VI, Kay, GN
  • Journal Title: Heart Rhythm 4(10) Pages: 1284-1291
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Preferential conduction across the ventricular outflow septum in ventricular arrhythmias originating from the aortic sinus cusp (2007)
  • Author(s): Yamada, T, Murakami, Y, Yoshida, N, Okada, T, Shimizu, T, Toyama, J, Yoshida, Y, Tsuboi, N, Muto, M, Inden, Y, Hirai, M, Murohara, T, McElderry, HT, Epstein, AE, Plumb, VI, Kay, GN
  • Journal Title: J Am Coll Cardiol 50(9) Pages: 884-891
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Acute and chronic effects of cardiac resynchronization in patients developing heart failure with long-term pacemaker therapy for acquired complete atrioventricular block. (2007)
  • Author(s): Shimano, M, Tsuji, Y, Yoshida, Y, Inden, Y, Tsuboi, N, Itoh, T, Suzuki, H, Muramatsu, T, Okada, T, Harata, S, Yamada, T, Hirayama, H, Nattel, S, Murohara, T
  • Journal Title: Europace 9(10) Pages: 869-874
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Electrophysiologic characteristics and outcome of segmental ostial superior vena cava isolation in patients with paroxysmal atrial fibrillation initiated by superior vena cava ectopy : comparison with pulmonary vein isolation (2007)
  • Author(s): Muto, M, Yamada, T, Murakami, Y, Okada, T, Okamoto, M, Shimizu, T, Toyama, J, Yoshida, Y, Tsuboi, N, Ito, T, Kondo, T, Inden, Y, Hirai, M, Murohara, T
  • Journal Title: J Electrocardiol 40(4) Pages: 319-325
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prevalence and severity of left atrial edema detected by electron beam tomography early after pulmonary vein ablation (2007)
  • Author(s): Okada, T, Yamada, T, Murakami, Y, Yoshida, N, Ninomiya, Y, Shimizu, T, Toyama, J, Yoshida, Y, Ito, T, Tsuboi, N, Kondo, T, Inden, Y, Hirai, M, Murohara, T
  • Journal Title: J Am Coll Cardiol 49(13) Pages: 1436-1442
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Non-pulmonary vein epicardial foci of atrial fibrillation identified in the left atrium after pulmonary vein isolation (2007)
  • Author(s): Yaxnada T
  • Journal Title: Pacing Clin Electrophysiol 30 Pages: 1323-1330
  • Peer Reviewed
• [Journal Article] Electrophysiologic and electrocardiographic characteristics and radiofrequency catheter ablation of focal atrial tachycardia originating from the left atrial appendage (2007)
  • Author(s): Yamada T
  • Journal Title: Heart Rhythm. 4 Pages: 1284-1291
  • Peer Reviewed
• [Journal Article] Electrophysiologic characteristics and outcome of segmental ostial superior versa cava isolation in patients with paroxysmal atrial fibrillation initiated by superior vena cava ectopy: comparison with pulmonary vein isolation (2007)
  • Author(s): Muto M
  • Journal Title: J Electrocardiol 40 Pages: 319-325
  • Peer Reviewed
• [Journal Article] Increase in electrocardiographic R-waves after revascularization in patients with acute myocardial infarction. (2006)
  • Author(s): Isobe S
  • Journal Title: Circ J 70 Pages: 1385-1391
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Dces RV lead positioning provide additional benefit to cardiac resynchronization therapy in patients with advanced heart failure? (2006)
  • Author(s): Shimano M
  • Journal Title: Pacing Clin Electrophysiol 29 Pages: 1069-1074
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Clinical protocol for angiogenesis by intramyocardial injection of autologous bone marrow mononuclear cells in patients with severe coronary artery disease: TACT-NAGOYA-HEART. (2006)
  • Author(s): Izawa H
  • Journal Title: Circ J 70 Pages: 1180-1183
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Increase in electrocardiographic R-waves after revascularization in patients with acute myocardial infarction (2006)
  • Author(s): Isobe, S, Takada, Y, Ando, A, Ohshima, S, Yamada, K, Nanasato, M, Unno, K, Ogawa, T, Kondo, T, Izawa, H, Inden, Y, Hirai, M, Murohara, T
  • Journal Title: Circ J 70(11)
  • NAID: 110004858624
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Does RV lead positioning provide additional benefit to cardiac resynchronization therapy in patients with advanced heart failure (2006)
  • Author(s): Shimano, M, Inden, Y, Yoshida, Y, Tsuji, Y, Tsuboi, N, Okada, T, Yamada, T, Murakami, Y, Takada, Y, Hirayama, H, Murohara, T
  • Journal Title: Pacing Clin Electrophysiol 29(10) Pages: 1069-1074
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinical protocol for angiogenesis by intramyocardial injection of autologous bone marrow mononuclear cells in patients with severe coronary artery disease : TACT-NAGOYA-HEART (2006)
  • Author(s): Izawa, H, Kondo, T, Usui, A, Yamamoto, K, Shintani, S, Inden, Y, Isobe, S, Unno, K, Kajiguchi, M, Kato, T, Noda, A, Okumura, K, Naoe, T, Takamatsu, J, Komori, K, Ueda, Y, Murohara, T
  • Journal Title: Circ J 70(9) Pages: 1180-1183
  • NAID: 110004814895
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Pioglitazone,a Peroxisome Proliferator-Activated Receptor-gamma Agonist, Attenuates Atrial Fibrosis and Atrial Fibrillation Promotion due to Congestive Heart Failure in Rabbits (2007)
  • Author(s): Shimano H
  • Organizer: Heart Rhythm 2007
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 2007-05-09
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Pioglitazone, a Peroxisome Proliferator-Activated Receptor-o Agonist, Attenuates Atrial Fibrosis and Atrial Fibrillation Promotion due to Congestive Heart Failure in Rabbits (2007)
  • Author(s): Shimano, M, Tsuji, Y, Inden, Y, Kitamura, K, Uchikawa, T, Harata, S, Nattel, S, Murohara, T
  • Organizer: Heart Rhythm 2007
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 2007-05-09
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Pioglitazone, a Peroxisome Proliferator-Activated Receptor-gamma Agonist, Attenuates Atrial Fibrosis and Atrial Fibrillation Promotion due to Congestive Heart Failure in Rabbits (2007)
  • Author(s): Shimano H
  • Organizer: Heart Rhythm 2007
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 2007-05-09